Genová terapie u kardiovaskulárních chorob

Cor Vasa 2003, 44(7-8):387-392

Gene therapy in cardiovascular disease

Pavel Gregor: III. interní-kardiologická klinika, Fakultní nemocnice Královské Vinohrady a 3. lékařská fakulta Univerzity Karlovy, Praha, Česká republika

In cardiology, gene therapy (GT) is focused on three main areas. These include neoangiogenesis, heart failure, and an effort to prevent re-occlusion following percutaneous transluminal intervention. Forty-seven percent of GT studies used non-viral vectors, bare DNA in 39% and liposome carriers in 8%. Maximum use was made of the gene-encoding vascular endothelial growth factor (VEGF) administered by intravascular, intramuscular, as well as intracoronary and intramyocardial routes, basic fibroblast growth factor (bFGF) and/or hepatic growth factor (HGF).
It was not until recently that viral vectors were used in the hope to provide more marked and prolonged gene expression (adenoviruses). However, the vector is not likely to find widespread use in human medicine. The reasons include limited duration of gene expression and problems related to its multiple administration because of the formation of neutralizing adenovirus antibodies. Development of myocarditis after this type of transmission has not been reported.
As regards individual studies, we now have at our disposal only results of experimental trials or phase I studies focused primarily on the safety of administration and only later, and to a smaller extent, on the therapeutic effect as such. The first and most important area of GT is enhanced angioneogenesis, referred to as therapeutic angiogenesis. Therapeutic angiogenesis may play a role particularly in severe myocardial ischemia with refractory angina not allowing to perform complete surgical and/or catheter-based revascularization (the same applies to ischemic lower limb syndromes).
The first pieces of evidence demonstrating the efficacy of GT in angioneogenesis were furnished by Takeshita in his experimental studies published in 1994, and by Isner first reporting his human cardioangiology studies in 1991-1996. These studies are consistent with previously findings that the muscle, and ischemic muscle in particular, is eager to receive DNA plasmids, most likely because of their multinuclear structure. Intramyocardial administration from the epicardial approach, occasionally under the control by esophageal echocardiography, does not pose a problem. Prolonged gene expression does not seem to be a basic requirement in GT aimed at myocardial neovascularization. The safety profile of transient gene expression has been tested in a variety of studies addressing myocardial ischemia. Three deaths were observed among 85 patients receiving plasmid-based gene transfer. Over a 1- to 3-year period of follow-up of 97 patients using adenovirus vector, there were 5 deaths; an incidence of more than 1,000 patients receiving conventional medical therapy or laser revascularization.
Another potential therapeutic indication for GT in cardiology is heart failure. In this context, there are three main directions of GT seeking to increase enhance contractility, by (1) modulating calcium homeostasis, (2) modulating beta-adrenergic receptors, and, finally, (3) increasing cardiomyocyte resistance to apoptosis.
Another possibility for GT use is prevention of restenosis following PTCA with or without stent use. Other potential applications of GT in cardiovascular disease include conversion of ventricular myocardial myocytes into pacemaker cells by means of the gene encoding the potassium channel; with potential uses envisaged for systemic and pulmonary hypertension GT.
In cardiology, GT seems to hold promise particularly in the treatment of ischemic injury. Given the absence of paucity of randomized, placebo-controlled studies, it is not possible to evaluate the effect of this therapeutic option. An optimal vector is to be found, and the most appropriate approach (presumably transmyocardial, possibly complemented with i. v. administration) and dose are to be defined in the future. Studies conducted to date seem to suggest GT is well tolerated in cardiology and safe, and allows to usher in to an extent greater than to date, an era of randomized, placebo-controlled trials.